Evidence that factors other than 1,25 dihydroxyvitamin D may play a role in augmenting intestinal calcium absorption in patients with primary hyperparathyroidism

Summary We examined 17 patients with primary hyperparathyroidism for their serum 1,25 dihydroxyvitamin D levels and for their fractional intestinal calcium absorption rates using a whole body counter and calcium-47. As controls, 10 normal volunteers were examined both before and after administration of 1α-hydroxyvitamin D to increase serum 1,25 dihydroxyvitamin D. Values of serum 1,25 dihydroxyvitamin D were 71.6±37.6 pg/ml (mean ±SD) in patients with primary hyperparathyroidism and 75.3±27.7 pg/ml (mean ±SD) in normal volunteers after administration of 1α-hydroxyvitamin D, while values of intestinal calcium absorption rate were 61.5±16.5% (mean ±SD) in patients with primary hyperparathyroidism and 34.1±5.1% (mean ±SD) in normal controls, respectively. There was a positive correlation between values of serum 1,25 dihydroxyvitamin D and intestinal calcium absorption in both groups. However, in patients with primary hyperparathyroidism, intestinal calcium absorption was more increased than that in normal volunteers when compared to their serum values of 1,25 dihydroxyvitamin D. This suggests that another factor than 1,25 dihydroxyvitamin D plays an important role in the intestinal calcium absorption in patients with primary hyperparathyroidism.     

Involvement of presurgical pain in preemptive analgesia for orthopedic surgery: a randomized double blind study

Preemptive analgesia (PA) is effective in animal models but its clinical effectiveness remains controversial. We examined the effect of preexisting pain on PA. Subjects were recruited from patients needing orthopedic surgery. Some had presurgical pain (fracture surgery and arthritic surgery), while others had no presurgical pain (removal surgery for a tumor, nail or plate). Epidural morphine or a saline control was given preemptively before surgery and maintained until skin closure. Following skin closure, naloxone or placebo was injected intravenously to erase the aftereffects of the morphine. After total recovery, the PCA pump was set to inject epidural morphine. Pain intensity after surgery was measured by a visual analogue scale (VAS), and the amount of morphine used within 48h after surgery. PA was significantly effective for removal surgery, but ineffective for fracture or arthritic surgery. For the fracture and arthritic surgery PA treatment groups, there was a significant correlation between pre- and postsurgical (6h) spontaneous pain, while the corresponding control groups showed no significant correlation. Postsurgical VAS values in the fracture and arthritic surgery control groups increased significantly compared with presurgical VAS values. PA was effective when presurgical pain was absent, but ineffective when presurgical pain was present. We propose that central sensitization is already established by presurgical pain, and preserved until the termination of surgery. The ineffectiveness of PA did not depend on whether the pain was acute (fracture surgery) or chronic (arthritic surgery).     

Storage of platelets in a novel additive solution (M-sol), which is prepared by mixing solutions approved for clinical use that are not especially for platelet storage

BACKGROUND: To reduce adverse reactions due to platelet (PLT) transfusion, medical solutions on the market, such as saline and ACD-A, are used to replace the plasma of PLT concentrates in Japan; however, they are not strongly preservative. Here, an attempt was made to develop a novel additive solution (M-sol) having the ability to preserve PLTs stably, with only approved solutions for clinical use. STUDY DESIGN AND METHODS: M-sol is a mixture of solutions for medical use, which consists of 77 mmol per L NaCl, 3 mmol per L KCl, 1 mmol per L CaCl2, 21 mmol per L Na acetate, 15 mmol per L glucose, 9.4 mmol per L Na3 citrate, 4.8 mmol per L citric acid, 44 mmol per L NaHCO3, and 1.6 mmol per L MgSO4. The in vitro variables of PLTs stored in M-sol, Seto-sol, PASIIIM, or 100 percent plasma were compared during 14 days of storage. RESULTS: The in vitro parameters (pH, P-selectin, %hypotonic shock response, %disk, mean PLT volume, aggregability) of PLTs were better maintained in M-sol containing 3 percent plasma than in 100 percent plasma, PASIIIM with 31 percent plasma, and Seto-sol with 3 percent plasma during 14 days of storage. CONCLUSION: The 2-week storage of PLTs in M-sol is feasible in terms of the in vitro PLT function. Our results here show that the additive solution, with a high ability to preserve PLTs, can be prepared by mixing solutions approved for clinical use that are not specifically for PLT storage.     

Variation of interleukin 8 -251 A>T polymorphism in worldwide populations and intra-ethnic differences in Japanese populations

BACKGROUND: Interleukin-8 (IL8) is a member of the family of chemokines. The IL8 gene has polymorphic variations, and the genotype of IL8 -251 A>T is associated with smoking behavior and cancer progression. METHOD: IL8 -251 A>T polymorphism were investigated in Japanese, from 5 different areas, in Ovambo, Turkish, Mongolian and Korean populations by PCR with confronting 2-pair primers (PCR-CTPP) analysis. RESULTS: A subpopulation analysis of Japan revealed a north-to-south increase in the frequency of the IL8 -251 T allele. Among the 5 groups, the Japanese showed the highest frequency of mutant allele followed by the Turks. The distribution pattern in the Japanese was different from those of Mongolians and Koreans. In the Ovambo population, no mutant allele homozygote subject was found and the frequency of mutant alleles was the lowest, similar to that in Gambians. CONCLUSION: The present study is the first to demonstrate the Japan population inter-prefecture differences in IL8 -251 A>T polymorphism as well as a certain genetic heterogeneity in the worldwide distribution of IL8 -251 A>T polymorphism. The distribution results may help define the true significance of IL8 -251 A>T polymorphism as a marker for smoking behavior in populations worldwide.     

Lysosomal membrane permeabilization causes secretion of IL-1β in human vascular smooth muscle cells

Objective

IL-1β secretion by the inflammasome is strictly controlled and requires two sequential signals: a priming signal and an activating signal. Lysosomal membrane permeabilization (LMP) plays a critical role in the regulation of NLRP3 inflammasome, and generally acts as an activating signal. However, the role of LMP controlling NLRP3 inflammasome activation in human vascular smooth muscle cells (hVSMCs) is not well defined.

Methods

LMP was induced in hVSMCs by Leu-Leu-O-methyl ester. Cathepsin B was inhibited by CA-074 Me. Cytokine release, mRNA, and protein were quantified by enzyme-linked immunosorbent assay, quantitative PCR, and Western blot, respectively. NF-κB activity was analyzed by immunostaining of the NF-κB p65 nuclear translocation and using the dual-luciferase reporter assay system.

Results

LMP had both priming and activating roles, causing an upregulation of proIL-1β and NLRP3 and the secretion of mature IL-1β from unprimed hVSMCs. LMP activated the canonical NF-κB pathway. The priming effect of LMP was inhibited by CA-074 Me, indicating an upstream role of cathepsin B.

Conclusions

These data support a novel role of LMP as a single stimulus for the secretion of IL-1β from hVSMCs, implying the possibility that hVSMCs are an important initiator of the sterile inflammatory response caused by lysosomal disintegration.

     

Noninvasive vessel-selective perfusion imaging with intravenous myocardial contrast echocardiography.

BACKGROUND: Intravenous myocardial contrast echocardiography (MCE) cannot identify each perfusion area of coronary vessels separately. However, by destroying microbubbles passing through a specific vessel using high-power ultrasound during intravenous MCE, vessel-selective perfusion imaging (VSPI) may be feasible. METHODS: In 10 open-chest dogs, intermittent short-axis images were obtained during contrast agent infusion using an ultrasound system. For VSPI, a probe coupled to another ultrasound machine was placed on the proximal left circumflex coronary artery (LCx). High-power ultrasound pulses were transmitted to destroy bubbles passing through the LCx. A negative contrast area on VSPI was considered to represent the perfusion area of the LCx (LCx-VSPI). A negative contrast area on conventional MCE during LCx occlusion and a region without staining by Evans blue dye were used as gold standards for defining the LCx perfusion area. LCx-VSPI was compared with a negative contrast area on conventional MCE during LCx occlusion and a region without staining by Evans blue dye. RESULTS: Despite lack of LCx occlusion, high-power destructive pulses produced a definite area of negative contrast on the LCx region. Decreased power of ultrasound pulses resulted in disappearance of the negative contrast area. An excellent relationship was demonstrated between both LCx-VSPI and a negative contrast area on conventional MCE during LCx occlusion (r = 0.93, P <.0001), and LCx-VSPI and a region without staining by Evans blue dye (r = 0.92, P =.0002). CONCLUSION: VSPI during intravenous MCE may be feasible for noninvasive assessment of perfusion areas associated with specific vessels.     

Beneficial effect of a prone position for patients with hypoxemia after transthoracic esophagectomy

OBJECTIVE: Although the prone position has been reported to improve arterial oxygenation in patients with acute respiratory distress syndrome, there have been no reports on its efficacy in patients with hypoxemia after transthoracic esophagectomy with three-field lymphadenectomy. This study was undertaken to assess the efficacy of the prone position on hypoxemia after three-field lymphadenectomy for thoracic esophageal carcinoma. DESIGN: Prospective randomized clinical study. SETTING: General intensive care unit at a university hospital. INTERVENTIONS AND MEASUREMENTS: Sixteen patients who underwent three-field lymphadenectomy and showed hypoxemia (PaO2/FiO2 ratios of <200 under positive end-expiratory pressure of >5 cm H2O) on the fifth postoperative day were randomly assigned to prone (eight patients) and nonprone (eight patients) groups. Prone position for 6 hrs was carried out for four consecutive days. The PaO2/FiO2 ratio, the duration of ventilatory support, and length of stay, were measured. RESULTS: Oxygenation: The PaO2/FiO2 ratio markedly increased by 32% +/- 22% in seven of eight patients (p <.05) when the patients were moved from the supine to the prone position. The PaO2/FiO2 ratio after the fourth prone position (238 +/- 55, p <.05) was significantly higher than that before the first trial of prone position (166 +/- 25) in these seven patients. Duration of ventilatory support and intensive care unit length of stay: Both the ventilation period (11.6 +/- 2.2 vs. 14.0 +/- 1.6 days, p =.0029) and the length of stay in the intensive care unit (12.8 +/- 4.4 vs. 17.2 +/- 3.4 days, p =.0032) were significantly shorter in the prone group compared with the nonprone group. The PaO2/FiO2 ratio at the time of cessation of prone positioning was significantly higher than the corresponding value in the nonprone group. CONCLUSION: In hypoxemic patients after three-field lymphadenectomy, the prone position improved arterial oxygenation without any deleterious effects. The beneficial effect of the prone position is possibly attributable to opening of the bronchi obstructed by secretions.     

TRPA1‐expressing primary afferents synapse with a morphologically identified subclass of substantia gelatinosa neurons in the adult rat spinal cord

The TRPA1 channel has been proposed to be a molecular transducer of cold and inflammatory nociceptive signals. It is expressed on a subset of small primary afferent neurons both in the peripheral terminals, where it serves as a sensor, and on the central nerve endings in the dorsal horn. The substantia gelatinosa (SG) of the spinal cord is a key site for integration of noxious inputs. The SG neurons are morphologically and functionally heterogeneous and the precise synaptic circuits of the SG are poorly understood. We examined how activation of TRPA1 channels affects synaptic transmission onto SG neurons using whole‐cell patch‐clamp recordings and morphological analyses in adult rat spinal cord slices. Cinnamaldehyde (TRPA1 agonist) elicited a barrage of excitatory postsynaptic currents (EPSCs) in a subset of the SG neurons that responded to allyl isothiocyanate (less specific TRPA1 agonist) and capsaicin (TRPV1 agonist). Cinnamaldehyde evoked EPSCs in vertical and radial but not islet or central SG cells. Notably, cinnamaldehyde produced no change in inhibitory postsynaptic currents and nor did it produce direct postsynaptic effects. In the presence of tetrodotoxin, cinnamaldehyde increased the frequency but not amplitude of miniature EPSCs. Intriguingly, cinnamaldehyde had a selective inhibitory action on monosynaptic C‐ (but not Aδ‐) fiber‐evoked EPSCs. These results indicate that activation of spinal TRPA1 presynaptically facilitates miniature excitatory synaptic transmission from primary afferents onto vertical and radial cells to initiate action potentials. The presence of TRPA1 channels on the central terminals raises the possibility of bidirectional modulatory action in morphologically identified subclasses of SG neurons.     

Regression of glomerular injury by losartan in experimental diabetic nephropathy

Many features of chronic kidney disease may be reversed, but it is unclear whether advanced lesions, such as adhesions of sclerotic glomerular tufts to Bowman's capsule (synechiae), can resolve during treatment. We previously showed, using a renal ablation model, that the renoprotective effect of the AT-1 receptor blocker, losartan, is dose-dependent. Here we determined if moderate and advanced glomerular lesions, associated with streptozotocin-induced diabetes, regress with conventional or high-dose losartan treatment. Using daily insulin injection for 10 months, we maintained diabetic adult male Munich-Wistar rats in a state of moderate hyperglycemia. Following this period, some rats continued to receive insulin with or without conventional or high-dose losartan for an additional 2 months. Diabetic rats pretreated with insulin for 10 months and age-matched non-diabetic rats served as controls. Mesangial expansion was found in the control diabetic rats and was exacerbated in those rats maintained on only insulin for an additional 2 months. Conventional and high-dose losartan treatments reduced this mesangial expansion and the severity of synechiae lesions below that found prior to treatment; however, the frequency of the latter was unchanged. There was no dose-response effect of losartan. Our results show that regression of mesangial expansion and contraction of sclerotic lesions is feasible in the treatment of diabetes, but complete resolution of advanced glomerulosclerosis may be hard to achieve.